Hexahydro pyrazinoquinolines

ABSTRACT

Various 8-methyl and 8-hydroxymethyl-2,3,4,4a,5,6-hexahydro-1Hpyrazino-(1,2-a)-quinolines having either nitro cyano or halogen substituted at the 7- or 9-position of the molecule and the 3allyl, 3-alkyl having 1 to 5 carbon atoms, 3-hydroxyalkyl having 2 to 6 carbon atoms, 3-cyanoalkyl having up to 6 carbon atoms in the alkyl moiety, 3-alkanoylalkyl having from 2 to 6 carbon atoms in the oxyalkyl moiety and up to 6 carbon atoms in the alkanoyl moiety, 3-cycloalkyl having up to 6 carbon atoms, 3-phenylalkyl having up to 3 carbon atoms in the alkyl moiety, 3-carboxyalkyl having up to 6 carbon atoms in the alkyl moiety, 3-alkanoyl having up to 6 carbon atoms, 3-carboxyalkanoyl having up to 6 carbon atoms, 3-carboxyacrylyl, 3-benzoyl, 3-furoyl, 3-thenoyl, 3-phthaloyl, 3-picolinoyl, 3-phenylacetyl, 3-carboxy, 3carbamoyl, 3-thiocarbamoyl and the 3-carbalkoxy having from 1 to 12 carbon atoms in the alkyl moiety derivatives thereof, their preparation and their utility as anti-schistosomal agents. Typical members include 7-chloro-8-methyl-2,3,4,4a,5,6-hexahydro1H-pyrazino-(1,2,-a)-quinoline and 8-hydroxymethyl-9-chloro2,3,4,4a,5,6-hexahydro-1H-pyrazino-(1,2,-a) -quinoline.

United States Patent 1191 Richards Aug. 12, 1975 1 HEXAHYDRO PYRAZINOQUlNOLINES [75] Inventor: Hugh C. Richards, Canterbury,

England [73] Assignee: Pfizer Inc., New York, NY. 22] Filed: Dec. 5, 1973 [21] Appl. No.: 422,087

Related US. Application Data [63] Continuation of Ser. No. 789,610, Jan. 7, 1969,

abandoned.

[30] Foreign Application Priority Data Jan. 12, 1968 United Kingdom 1853/68 Aug. 2, 1968 United Kingdom 36884/68 [52] US. CL... 260/268 TR; 260/287 R; 260/288'R; 260/289 R; 424/250 [51] Int. Cl. C07D 295/08 [58] Field of Search 260/268 TR [56] References Cited UNITED STATES PATENTS 3,647,791 3/1972 Rossi et a1. 260/268 TR OTHER PUBLICATIONS Rossi et al., Chemical Abstracts, Vol. 70, 47500y, 1969.

Primary Examiner-Donald G. Daus Assistant Examiner1ose Tovar Attorney, Agent, or Firm-Connolly and Hutz [57] ABSTRACT Various S-meth'yl and 8-hydroxymethyl-2,3,4,4a,5,6- hexahydro- 1 H-pyrazino-[ 1,2-a]-quinolines having either nitro cyano or halogen substituted at the 7- or 9- position of the molecule and the 3-allyl, 3-alkyl having 1 to 5 carbon atoms, 3-hydroxyalkyl having 2 to 6 carbon atoms, 3-cyanoalkyl having up to 6 carbon atoms in the alkyl moiety, 3-alkanoylalkyl having from 2 to 6 carbon atoms in the oxyalkyl moiety and up to 6 carbon atoms in the alkanoyl moiety, 3-cycloalkyl having up to 6 carbon atoms, 3-phenylalkyl having up to 3 carbon atoms in the alkyl moiety, 3-carboxyalkyl having up to 6 carbon atoms in the alkyl moiety, 3- alkanoyl having up to 6 carbon atoms, 3-carboxyalkanoyl having up to 6 carbon atoms, 3-carboxyacrylyl, 3-benzoyl, 3-furoyl, 3-thenoyl, 3-phthaloyl, 3- picolinoyl, 3-phenylacetyl, 3-carboxy, 3-carbamoy1, 3-thiocarbamoyl and the 3-carbalkoxy having from 1 to 12 carbon atoms in the alkyl moiety derivatives thereof, their preparation and their utility as antischistosomal agents. Typical members include 7- chloro-8-methyl-2,3,4,4a,5,6-hexahydrol H-pyrazino- [l,2,-a]-quinoline and 8-hydroxymethyl-9-chloro- 2,3,4,4a,5,6-hexahydro-1H-pyrazino-[ 1 ,2,-a]- quinoline.

3 Claims, No Drawings m qw-rmmdeelvu mm) lMYbNnn-MW HEXAHYDRO PYRAZINOQUINOLINES CROSS-REFERENCE TO RELATED APPLICATION This application is a continuation of application Ser.

, No. 789,610 filed Jan. 7, 1969 and now abandoned.

BACKGROUND OF THE INVENTION :This invention relates to certain new and useful hexahydro pyrazine-quinoline compounds of principal interest to those in the field of chemotherapy. More particularly, it is concerned with various novel substituted hexahydro pyrazinoquinolines and their non-toxic acid addition salts, which are of especial value in view of their anti-schistosomal properties.

In the past, various attempts have been made by numerous investigators in this particular field of therapy to obtain new and still better forms of agents and/or methods for the treatment of schistosomiasis. In many instances, these efforts have further involved the synthesis and testing of various new organic compounds, particularly in the category of nitrogen heterocycles. For instance, in British Pat. No. 837,306, there is disclosed a series of dicarboxylic acid monopiperazides with a 3-halogen4-methylphenyl moiety located at the l-position of the piperazine ring that are reported as being active against schistosomiasis. However, little is known about the effect of other di-nitrogen heterocycles in this area and the existing therapy, unfortunately, still suffers from a number of known drawbacks such as, e.g., relatively low potency (requiring more than a single dose of therapy), problems of toxicity, the lack of a demonstrated prophylactic effect, etc.

SUMMARY OF THE INVENTION andthepharmaceutically acceptable acid addition salts thereof, wherein R is a member selected from the group consisting of hydrogen, allyl, alkyl havingfrom l to 5 carbon atoms, hydroxyalkyl having from 2 to 6 carbon atoms, cyanoalkyl having up to 6 carbon atoms in the alkyl moiety, alkanoyloxyalkyl having from 2 to 6 carbon atoms in the oxyalkyl moiety and up to 6 carbon atoms in the alkanoyl moiety, cycloalkyl having up to 6 carbon atoms, phenylalkyl having up to 3 carbon atoms in the alkyl moiety, carboxyalkylhaving up to 6 carbon atoms in 'the alkyl moiety, alkanoyl andcarboxyalkanoyl each having up to 6 carbon atoms, carboxyacrylyl, benzoyl, furoyl, thenoyl, phthaloyl, picoing of hydrogen and alkyl having from one to six carbon atoms; and the N-oxide derivatives of said base compounds where R, is other than hydrogen. These compounds all possess anti-schistosomal activity and are therefore, useful in the treatment of schistosomiasis and/or for the control of schistosome infections.

Of especial interestin this connectionare the preferred compounds of the present invention where R in the aforesaid structural formula is either hydrogen or an alkyl group containing from one to four carbon atoms, R is methyl or hydroxyrnethyl, R is nitro or chlorine located at either the 7- or 9-position of the molecule, R ishydrogen and R is hydrogen or methyl. Typical member compounds of the preferred class include such 7- or 9-nitro or chloro substituted 8-methyl- 2,3 ,4,4a,5 ,6-hexahydrol I-I-pyrazino-[ l,2-a]- quinolines as 8-methyl9-nitro-2,3,4,4a,5,6-hexahydro lI-I-pyrazino[ l,2-a]-quinoline, 3-n-propyl-8-methyl-9- nitro-2,3 ,4,4a,5 ,6-hexahydrol H-pyrazino-[ 1,2-a]- quinoline, 3-isopropyl-8-methyl-9-nitro-2,3,4,4a,5,6- hexahydrol I-I-pyrazino-[ l,2-a]-quinoline, 7-chloro-8- methyl-2,3,4,4a,5,6-heXahydro-l H-pyrazino-[ l ,2-a]- quinoline, 8-methyl-9-chloro-2,3,4,4a,5,6-hexahydrolH-pyrazino-[ l,2-a]-quinoline, 3,8-dimethyl-9-chloro- 2,3,4,4a,5,6-hexahydrol H-pyrazino-[ l,2-a]- quinoline, 8, l 0-dimethyl-9-chloro-2,3 ,4,4a,5 ,6- heXahydro-lH-pyrazino-[ l,2-a]-quinoline and 3-npropyl-8-methyl9-chloro-2,3,4,4a,5 ,6-hexahydrol H- pyrazino-[ l ,2-a]-quinoline, respectively, as well as the corresponding 8'hydroxymethyl compounds. These particular compounds are all highly potent as regards anti-schistosomal activity.

DETAILED DESCRIPTION OF THE INVENTION In accordance with the processes employed for preparing the novel compounds of this invention, various alternate methods are provided depending upon the specific structures of the actual final products desired. For instance, compounds of the invention in which R is hydrogen, R is methyl and R nitro or halogen are prepared starting from the appropriate 2-aminomethyl- 6-methyll ,2,3,4-tetrahydr0quinoline compound, which is cyclized with ethyl chloroacetate, chloroacetyl chloride, dimethyl oxalate or oxalyl chloride to give the corresponding 8-methyl-2,3,4,4a,5,6-hexahydro-l I-I- pyrazino-[ l,2-a]-quinoline-2-one or l,2-dione, as the case may be, followed by reduction with lithium aluminum hydride and then nitration with nitric acid in the presence of concentrated sulfuric acid. The aforementioned tetrahydroquinoline starting material may be prepared by catalytic hydrogenation of the corresponding known l-benzoyl-2-cyanol ,2-dihydro-o-methylquinoline, followed by acidic hydrolysis, or it can simply be obtained by catalytic reduction of the corresponding 6-methylquinoline-2-aldehyde in the presence of ammonia to give the intermediate 2-aminomethyl-6- methylquinoline, which is then further reduced by catalytic hydrogenation to afford the desired compound.

2-aminomethyl-6-methyl- 1 ,2,3,4-

In like manner, novel hexahydro pyrazinoquinoline compounds of the same type as indicated above may also be prepared from the aforementioned 2- aminomethyl-o-methylquinoline type compounds using bromoacetyl chloride as the cyclizing agent to yield the corresponding 8-methyl-2-oxo-2,3 ,4-trihydrol H- pyrazino-[ l ,2-a]-quinolinium bromide as intermediate, followed by catalytic reduction of the hetero-aromatic ring and lithium aluminum hydride reduction of the keto group to give the corresponding 8-methyl- 2,3 ,4,4a,5 ,o-hexahydrol H-pyrazino-[ 1,2-a]- quinoline, which can be nitrated as before. Other routes which may be employed here include l the cyclization of known lower alkyl 6-methyl-l ,2,3,4- tetrahydroquinoline-2-carboxylates with ethylene imine, followed by reduction with lithium aluminum hydride and then nitration, and (2) the cyclization of known 2-( B-hydroxyethylamino)methyl-6-methyll,2,3,4-tetrahydroquinolines with phosphorous pentachloride or phosphoric oxide to give the corresponding substituted hexahydro pyrazinoquinoline compound which can then be nitrated. In all instances, the resulting 7and 9-nitro compounds may be separated, if necessary, by means of fractional crystallization when in the form of a suitable salt.

On the other hand, novel compounds of the present invention in which R is other than hydrogen are simply prepared from those already obtained as aforesaid (where R, is hydrogen) by using synthetic methods well-known to those skilled in the art for substitution on the free hydrogen atom of secondary amines. These methods involve such diverse reactions as: (1) acylation to give 3-acyl derivatives; (2) acylation followed by reduction of the carbonyl group to give alkyl or aralkyl substituents; (3) direct alkylation, allylation or aralkylation; (4) reaction with unsaturated or halosubstituted lower alkanoic acids, or with their corresponding esters, amines, thioamides or nitriles; and (5) reaction with lower alkyl chloroformates, or with cyanates, thiocyanates, carbamoyl halides or thiocarbamoyl halides. Needless to say, such reactions as outlined above can be carried out before the final nitration step (when R is to be nitro), provided said nitration step does not interfere with the aforementioned R substituent. '1

Alternatively, substituted hexahydropyrazinoquinoline compounds of the invention in which R is alkyl, hydroxyalkyl, aralkyl or cycloalkyl may be prepared by simply introducing such a group into the 2-aminomethyl or 2-(B-hydroxyethylamino)- methyl-quinolines or tetrahydroquinoline starting materials, hereinbefore described and utilized for preparing those novel compounds where R is hydrogen. Hence, the substitution step would necessarily be carried out before the cyclization reaction and subsequent nitration in these particular instances. Suitable N- substituted Z-aminomethyl and/or 2-( B- hydroxyethylamino) methyl quinolines and tetrahydroquinolines required as starting materials in this alternate series of reactions may, in turn, be readily prepared starting from the appropriate o-methylquinoline- Z-carboxylic acid, 2-h'alomethyl-6-methylquinoline or 6-methylquinoline-Z-aldehyde, as the case may be, using methods that have previously been described and are illustrated in Examples XXVIXXX hereinafter.

Of course, when R is halogen in any of the aforementioned reactions, the final nitration step is omitted.

Needless to say, novel hexahydro pyrazinoquinoline compounds of the invention in which R is cyano or halogen rather than nitro, as previously described, can simply be prepared from the latter (i.e., where R is nitro) by reduction to the amine, followed by diazotisation and subsequent conversion to the 7- or 9-halo or cyano compounds, as the case may be, using wellknown methods of organic chemistry. On the other hand, compounds of the invention in which R is hydroxymethyl or formyl can be prepared from those where R is methyl by using an appropriate microorganism like Aspergillus sclerotiorum Huber (publicly available from the Centralbureau voor Schimmelcultures at Baarn, Holland) to effect such a change, whereby the methyl group is converted by oxidation to one of the other two groups during the course of the over-all fermentation, as illustrated by Example XXXI hereinafter.

The N-oxide derivatives of the compounds of this invention, i.e., N-oxide derivatives of the aforementioned novel substituted hexahydro pyrazinoquinolines in which R is other than hydrogen, may be prepared by simply using well-known synthetic methods to effect such a conversion from the parent compound, e.g., oxidation via 30% hydrogen peroxide or benzoyl peroxide, etc.

Inasmuch as the substituted hexahydro pyrazinoquinoline compounds of this invention all possess an asymmetric carbon atom at position 4a of the molecule, they may exist in separated dand optically active forms, as well as in racemic dlmixtures necessarily produced by the present synthetic methods as hereinbefore described. The invention contemplates the d, land racemic forms within its scope.

The acids which are used to prepare the pharmaceutically acceptable acid addition salts of this invention are those which form non-toxic acid addition salts containing pharmacologically acceptable anions, such as the hydrochloride and sulfate, when reacted with the aforementioned hexahydro pyrazinoquinoline base compounds. Preferred acids for use in this connection include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, tartaric acid, oxalic acid, gluconic acid, saccharic acid, benzoic acid, succinic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, picric acid, arnsonic acid (4,4'-diaminostilbene- 2,2 -disulfonic acid)'- and pamoic acid (Ll-methylenebis-2-hydroxy-3-naphthoic acid).

As previously indicated, the hexahydro pyrazinoquinoline compounds of this invention are therapeutically valuable as anti-schistosomal agents, particularly in view of their ability to move adult schistosome organisms from their normal sites in the mesenteric veins on to the liver. Hence, they are useful in the treatment of schistosomiasis and/or for the control of schistosome infections with the preferred compounds of this invention being especially useful in this connection in view of the highly potent nature of their anti-schistosomal action and lack of significant side effects. For instance, 3-isopropyl-8-methyl9-nitro- 2,3,4,-4a,5,6-hexahydrol H-pyrazino-[ l ,2-a1- quinoline maleatc, a typical and preferred agent of the present invention, has been found to be highly effective against .S'clzistosomu numsoni when administered orally to infected mice at a dosage level of 30 mg./kg. per day for a period of 4 days without causing any untoward side effects. Further, these herein described compounds can be administered as anti-schistosomal agents by either the oral or parenteral routes of administration. In general, they are ordinarily administered in dosages ranging from about 5.0 mg. to about 150 mg. per kg. of body weight per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen.

In connection with the use of the hexahydro pyrazinoquinoline compounds of this invention for the treatment of schistosomiasis, it is to be noted that these compounds may be administered either alone or in combination with pharmaceutically acceptable carriers by either of the two routes previously indicated, and that such administration can be carried out in both single and multiple dosages. More particularly, the novel compounds of this invention can be administered in wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspension, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, such oral pharmaceutical formulations can be suitable sweetened and/or flavored by means of various agents of the type commonly employed forjust such purposes. In general, the therapeutically useful compounds of thisinvention are present in such dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, i.e., in amounts which are sufficient to provided the desired unit dosage previously indicated.

For purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and dicalcium phosphate may be employed along with various disintegrants such as starch and preferably potato or tapioca starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules; preferred materials in this connection would also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.

For purposes of parenteral administration, solutions of these particular hexahydro pyrazinoquinolines in seasame or peanut oil or in aqueous-propylene glycol or N,N-dimethylformamide may be employed, as well as sterile aqueous solutions of the corresponding watersoluble, non-toxic mineral and organic acid addition salts previously enumerated (e.g., the methanesulfonate salt). Such aqueous solutions should be suitably buffered if necessary and the liquid dilutent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes. In this connection, the sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art.

This invention is still further illustrated by the following examples, which are not to be construed in any way or manner as imposing limitations upon the scope thereof.

EXAMPLE I A solution consisting of 200 g. of l-benzoyl-2-cyano- 6-methyl 1,2 dihydro-quinoline (prepared by the method of Reissert starting from 6-methyl-quino1ine and using benzoyl chloride and potassium cyanide as reagent) dissolved in one liter of ethyl acetate was hydrogenated in an autoclave at C. and 1,500 p.s.i.g. pressure in the presence of Raney nickel as catalyst for a period of 4 hours. The solution was then cooled to room temperature (-25C.), filtered and the solvent in the resulting filtrate removed by means of distillation in vacuo to afford 2-(N-benzoy1aminomethy1)-6-methyl- 1,2,3,4-tetrahydroquino1ine as a residual oil. The latter material crystallized on trituration with diethyl ether and was subsequently recrystallized from ethanol to give a pure product melting at 130132C.

The latter compound was then suspended in a solvent mixture consisting of 90% by volume of 5N hydrochloric acid and 10% by volume of ethanol, and refluxed overnight for a period of approximately 18 hours. After allowing to" cool to room temperature, the resulting mixture was made strongly basic with 5N sodium hydroxide, and the basic solution was thereafter extracted with diethyl ether and filtered. The insoluble material on the filter funnel was then dissolved in 2N hydrochloric acid, treated with alkali as before and extracted with diethyl ether. The combined ether extracts from both operations were then dried over anhydrous sodium sulfate and distilled under reduced pressure to give 2 aminomethyl-6-methyll ,2,3,4-tetrahydroquinoline as a residual oil (b.p. l26140C./O.4 mm. Hg.), which subsequently crystallized on standing to afford a solid product melting at 576lC.

A finely-ground powdered mixture was then prepared consisting of 8.8 g. (0.05 mole) of 2- aminomethyL-methyl- 1 ,2,3,4-tetrahydro-quinoline, obtained as described above, and 1 1.8 g. (0.10 mole) of dimethyl oxalate. The latter mixture was then heated in an open vessel on the steam bath for a period of 18 hours. The resulting brown mobile oil, obtained in this manner, was allowed to cool before treatment with 20 ml. of acetone. On boiling the latter mixture, followed by cooling, there was finally a white solid material as precipitate. The latter material was then recovered by means of filtration, washed with a little cold acetone and subsequently dried in vacuo to afford the desired product in crude form. Recrystallization from acetone then gave 2.5 g. of pure 8methyl-2,3,4,4a,5,6- hexahydrohydro-1H-pyrazine[ l ,2-a]-quino1ine-1 ,2- dione in the form of colorless needles, m.p. 213216C.

Ana]. Calcd. for C H N O C, 67.80; H, 6.10; N, 12.15. Found: C, 67.70; H, 6.10; N, 12.20.

The entire yield of 8-methy1-2,3,4,4a,5,6-hexahydrolH-pyrazino-l 1,2-a]-quin0line was next added portionwise to a slurry consisting of 1.1 g. of lithium aluminum hydride in m1. of dry dioxane at a temperature kept within the 7583C. range. Upon completion of this step, the mixture was stirred vigorously for 8 hours and then allowed to cool slowly to approximately 35C. At this point, water was carefully added to destroy excess hydride in the mixture and the crude product material was then poured into water and subsequently extracted from the resulting aqueous medium with diethyl ether (three separate extractions were necessary). After drying the ether extracts over anhydrous magnesium sulfate, followed by evaportation of same under reduced pressure, there was finally obtained 1.8 g. of crude 8- methyl-2,3 ,4,4a,5 ,6-hexahydrol H-pyrazino-[ l ,2-a]- quinoline as a brown mobile oil. Subsequent distillation of the latter material in vacuo then gave 1. 15 g. of pure product, which was a red viscous oil (b.p. 150C./ 1 mm. Hg.). Conversion of this material to the maleate derivative, for analytical purposes, then gave pure 8- me.thyl-2,3 ,4,4a,5 ,6-hexahydrol H-pyrazino-[ 1 ,2-a]- quinoline maleate, m.p. l5'7l58C.

Anal Calcd. for C H N O c, 64.15; H, 6.90; N, 8.80. Found: C, 64.15; H, 6.80; N, 8.75.

A solution of consisting of 0.315 g. of concentrated nitric acid ((1. 1.5) in 5 ml. of concentrated sulfuric acid was then prepared and added to a well-stirred, ice cold solution of 1.15 g. of 8-methy1-2,3,4,4a,5,6- hexahydro-lH-pyrazine-[ l,2-a]-quinoline in 25 ml. of concentrated sulfuric acid. The resulting mixture was then stirred at 5C. for an additional period of 4-5 hours. The crude nitrated product was poured into a mixture of ice and water, and subsequently made basic with solid potassium carbonate and filtered. Upon extraction of the resulting aqueous filtrate with chloroform and concentration of the combined chloroform extracts under. reduced pressure, there was ultimately obtained a 1.0 g. yield of an orange-red oil as the residual liquid. The latter material, which was essentially pure 8-methyl-9-nitro-2,3 ,4,4a,5 ,6-hexahydro-1H- pyrazino-[ l,2-a]-quinoline, was then taken up in ml. of ethyl acetate and mixed with a solution of 0.5 g. of maleic acid dissolved in 5 ml. of warm ethyl acetate. In this manner, there was obtained a canary yellow precipitate of the maleate salt, which was subsequently filtered and recrystallized from hot methanol to give 0.7 g. of pure 8-methyl-9-nitro-2,3,4,4a,5,6-hexahydrolH-pyrazino-[ l,2-a]-quinoline maleate in the form of golden yellow plates, m.p. 203204C.

Anal. Calcd. for C H N O C, 56.20; H, 5.80; N, 11.60. Found: C, 56.45; H, 5.80; N, 11.85.

EXAMPLE II To a warm solution of 42 g. of 2-formyl-6- methylquinoline in 200 ml. of ethanol, there were added 15 g. of ethanolamine in a cautious manner in view of the exothermic nature of the reaction. The resulting mixture was then refluxed for a period of 2 hours and l g. of activated charcoal was thereafter added. Refluxing was then continued for an additional 5 minutes before filtering the mixture while hot. On slow cooling of the filtrate to 0C., there was ultimately obtained a 48.6 g. yield of 2-(B- hydroxyethyliminomethyl)-6-methylquinoline in the form of small white needles, m.p. 147-l49C.

A solution consisting of 45 g. of 2-(B- hydroxyethyliminomethyl)-6-methylquinoline in 500 ml. of absolute ethanol was then prepared and subsequently hydrogenated over Raney Nickel (5 g.) at C. and 750 p.s.i.g. pressure fora period of 7 hours.

After removal of the catalyst by means of filtration and the solvent by means of evaporation under reduced pressure, there was obtained a pale yellow oil which soon solidified on standing. Recrystallization of the latter material from ethyl acetate then gave 32.5 g. of 2- (,B-hydroxyethylaminomethyl)-6-methyl- 1 ,2,3,4-

tetrahydroquinoline as a white solid, m.p. 88-88.5C.

The product obtained above, i.e., 23.4 g. of the material melting at 8888.5C., was then dissolved in 250 ml. of dry xylene and the resulting solution stirred vigorously while 48 g. of phosphoric oxide was rapidly added thereto, being washed into the reaction mixture with a further quantity of dry xylene (150 ml.). The stirred solution was then gradually heated to C. during a 2 /2 hour period and refluxed at that point for a further 24 hours. The spent mixture was then cooled and the xylene solution removed therefrom by means of decantation. Upon evaporation of the solvent under reduced pressure, a semi-solid residual material was obtained. The latter was then continually extracted with 5N hydrochloric acid until the extracts were no longer colored, and the combined extracts were subsequently basified with 5N sodium hydroxide solution before further extraction with three separate portions of diethyl ether (each of 250 ml. in volume). The combined ether extracts were again dried over anhydrous magnesium sulfate and filtered, with the filtrate being thereafter evaporated to yield a dark viscous oil. Fractional distillation of the latter material under reduced pressure, then gave 10.6 g. of 8-methyl-2,3,4,4a,5,6- hexahydro-lH-pyrazino-[ l,2-a]-quinoline as a colorless oil (b.p. l22l24C./0.25 mm. Hg), which soon solidified on standing. The product was identical in every respect with corresponding compound of Example I.

To a mixture of 50 ml. of benzene and 50 ml. of toluene, there were added 5 g. of the product obtained above, plus 4.0 ml. of formic acid and the resulting mixture was then refluxed for a period of 18 hours (the water which formed was collected in a Dean-Stark apparatus). An additional amount (4.0 ml.) of formic acid was then added and the mixture refluxed for a further 24 hours, before cooling to room temperature (-25C. After extracting with two-50 ml. portions of 2N hydrochloric acid and washing the combined extracts with diethyl ether, followed by basification of same with 2N sodium hydroxide solution, there was obtained a basic aqueous medium which was subsequently extracted with two-100 ml. portions of ethyl acetate. The combined organic extracts were then dried over anhydrous magnesium sulfate and filtered, and the resulting filtrate evaporated to near dryness under reduced pressure to afford an almost-white solid material. The latter material was then taken up in 20 ml. of chloroform and the resulting solution diluted with 20 ml. of petroleum ether (b.p. 4060C.) to give 4.4 g. of 3-formyl-8-methyl-2,3,4,4a,5,6-hexahydrolH-pyrazino-[ 1,2-a]-quinoline as a white solid precipitate, m.p. l l5l 16C.

A solution of 4.2 g. of the above product in 100 ml. of dry dioxane was then prepared and this solution was added to a rapidly stirred suspension of 5 g. of lithium aluminum hydride in ml. of dry dioxane over a 45- minute period. The resulting mixture was stirred for 5.5 hours, cooled and the excess reagent cautiously decomposed by the slow addition of water thereto. After removing solid impurities present by means of filtration and evaporating the resulting filtrate to near dryness while under vacuum (with the last traces of water being removed by means of azeotropic distillation with benzene), there was obtained a residual material which soon solidified on cooling. Subsequent recrystallization from petroleum ether (b.p. 4060C.) then gave 2.9 g. of 1 3,8-dimethyl-2,3,4,4a,5,6-hexahydro-lH-pyrazino- [1,2-a]-quinoline as colorless prisms melting at 9293C.

To above compound (2.5 g.) was then dissolved in 30 ml, of concentrated sulfuric acid by adding same to said acid over a 1-hour period and then stirring the mixture at C. until complete dissolution occurred. At this point, a solution consisting of 0.7 1 g. of nitric acid (d. 1.5), i.e., 0.48 ml., in 5 ml. of concentrated sulfuric acid was slowly added thereto during the course of a 20-minute period, with constant agitation, while maintaining the temperature of the reaction mixture at 05C. throughout the course of the addition step. After stirring the reaction mixture for a further 3 hours at 0-5C., the solution was poured unto ice and subsequently neutralized with sodium carbonate reagent. The product separated as a red-orange oil, together with some sodium sulfate crystals, and was collected by filtering and washing with chloroform. The chloroform layer was then separated and the aqueous layer extracted with another portion of chloroform. The combined chloroform extracts were then dried over anhydrous magnesium sulfate, filtered and the filtrate subsequently evaporated to afford a red-orange oil. The latter material which was essentially pure 3,8-dimethyl9- nitro-2,3 ,4,4a,5 ,6-hexahydrol H-pyrazino-[ 1,2-a]- quinoline, was then taken up in a minimum amount of ethyl acetate and added to a hot solution of 1.5 g. of maleic acid dissolved in 30 ml. of ethyl acetate. After cooling to room temperature and adding 50 ml. of dry diethyl ether to effect complete precipitation, the resulting solid was collected by means of filtration and recrystallized from ethyl acetate-methanol (4:1 by volume) to give 1.8 g. of 3,8dimethyl-9-nitro- 2,3 ,4,4a,5,6-hexahydrol H-pyrazino-[l ,2-a]-quinoline maleate as a yellow crystalline material, m.p. 182185C.

Anal. Calcd. for C H, N O .C H O C, 57.31; H, 6.00; N, 11,14. Found: C, 57.16; H, 6.21; N, 10.46.

EXAMPLE III A mixture consisting of 5.0 g. ,of 8-methyl- 2,3 ,4,4a,5,6-hexahydro- 1 H-pyrazino-[ 1,2-a]-quinoline in 25 ml. of acetic anhydride was refluxed for a 2 /2 hour period, and the resulting dark solution was then poured into ice-water (250 ml.). After allowing the precipitated solid to stand for one hour in the aqueous medium, it was subsequently extracted with 2-200ml. portions of ethyl acetate. The combined extracts were then ,washed with 10% sodium bicarbonated solution, followed by water and dried over anhydrous magnesium sulfate. On removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there was obtained a residual pink solid. Recrystallization of the latter material from petroleum ether (b.p. 6080C.) then gave 3.92 g. of 3-acetyl-8-methyl-2,3 ,4,4a,5 ,6-hexahydro-1H- pyrazino-ll,2-a]-quinoline as white prisms melting at 127-l28C.

The above product (3.5 g.) was then reduced by lithium aluminum hydride in the manner of the previous example and after purification by distillation under reduced pressure, there was obtained a 2.0 g. yield of 3- ethyl-8-methyl-2,3,4,4a,5 ,6-hexahydro- 1 H-pyrazino- [1,2-a]-quinoline (b.p. l30C./0.30 mm. Hg), which soon solidified to give a colorless material of melting point 5657C.

Nitration of 1.98 g. of 3-ethyl-8-methyl-2,3,4,4a,5,6- hexahydrol H-pyrazino-[ l,2-a]-quinoline was then carried out with nitric-sulfuric acid as reagent in the same manner as described in the previous example for the nitration of the corresponding 3,8-dimethyl compound. in this particular case, the product obtained was 3-ethyl-8-methyl-9-nitro-2,3 ,4,4a,5 ,6-hexahydrol H- pyrazino-[1,2-a]-quinoline, which after conversion to the maleate and recrystallization from ethyl acetatemethanol 10:1 by volume) gave 1.0 g. of pure 3-ethyl- 8-methyl-9-nitro-2,3 ,4,4a,5 ,6-hexahydro- 1 H-pyrazino- [l,2-a]-quinoline maleate in the form of yellow needles, m.p. l72173C.

Anal. Calcd. for C, =,H N O .C H O C, 58.30; H, 6.44; N, 10.74. Found: C, 58.54; H, 6.50; N, 11.26.

EXAMPLE IV A solution consisting of 10 g. of 2-chloromethyl-6- methylquinoline and 16.2 g. of N- isopropylaminoethanol dissolved in 100 m1. of absolute ethanol was refluxed for a period of 6 hours. The alcohol solvent was then removed in vacuo and the residual oil basified with 2N sodium hydroxide solution, followed by subsequent extraction with chloroform. The combined chloroform extracts were dried over anhydrous magnesium sulfate, filtered and the resulting filtrated evaporated under reduced pressure to give a black viscous oil, which on subsequent distillation afforded 9.4 g. of 2-N-( ,B-hydroxyethyl )-N- isopropylaminomethyl--methylquinoline as a thick red oil, b.p. 155l58C./0.25 mm. Hg.

A solution of 8 g. of the above product in 100 ml. of absolute ethanol was then hydrogenated over 3 g. of Raney Nickel at C. and 750 p.s.i.g. pressure for a period of 3.5 hours. After removal of the catalyst by means of filtration and the alcohol solvent on evaporation in vacuo, there was obtained a 7.2 g. yield of 2-N- (B-hydroxyethyl)-N-isopropylaminomethyl-6-methyl- 1,2,3,4-tetrahydroquinoline in the form of a green viscous oil.

To a well-stirred solution consisting of 6.1 g. of 2-N- (B-hydroxyethyl)-N-isopropylaminomethyl-6-methyl- 1,2,3,4-tetrahydroquinoline in ml. of dry xylene, there were added 10.6 g. of phosphoric oxide and the resulting mixture heated to reflux during the course of a 2 /2 hour period. After refluxing for a further 10 hours, the mixture was cooled and the xylene subsequently removed therefrom by decantation. The resulting semi-solid mass was then dissolved in 5N- hydrochloric acid, and thereafter basified with 5N sodium hydroxide solution before extraction with diethyl ether. The dried ethereal extracts were then evaporated to near dryness under reduced pressure to give a black oil residue, which on subsequent distillation in vacuo afiorded 1.3 g. of 3-isopropyl-8-methyl- 2,3,4,4a,5 ,6-hexahydro-1H-pyrazino-l l,2-a]-quinoline in the form ofa colorless oil, b.p. 156-160C./1.0 mm. Hg.

To 1.05 g. of the above product in 20 ml. of concentrated sulfuric acid at 0C., there were added 1.18 ml. of fuming nitric acid in 2.0 ml. of concentrated sulfuric acid at 3C., with constant agitation being maintained throughout the addition step which required approximately 1.5 hours. The resulting mixture was then stirred at 03C. for a period of 4 hours, before pouring unto crushed ice and basifying with solid potassium carbonate. The oily product so obtained was thereafter extracted with chloroform and the combined chloroform extracts were subsequently dried and evaporated under reduced pressure to a brown oil of 1.5 g. yield. The latter material was dissolved in ml. of ethyl acetate and then treated with a warm solution of maleic acid in ethyl acetate (0.6 g. of said acid in 5 ml. of solvent) to give a canary yellow solid as precipitate. Recrystallization of the latter material from hot ethyl acetate-methanol (:1 by volume) afforded 0.7 g. of 3- isopropyl-8-methyl-9-nitro-2 ,3 ,4,4a,5 ,6-hexahydro- 1H-pyrazino-[1,2-a]-quinoline maleate in the form of golden yellow needles, m.p. l49l50C.

Anal. Calcd. for C H N O C H O C, 66.60; H, 7.77; N, 7.83. Found: C, 66.41; H, 7.44; N, 7.83.

EXAMPLE V The procedure described in Example 111 was repeated except that propionic anhydride was substituted for acetic anhydride as reagent in the first stage and there was ultimately obtained, in this manner, a 0.9 g. yield of 3-n-propy1-8-methyl-9-nitro-2,3,4,4a,5,6- hexahydrol H-pyrazino-[ 1,2-a]-quinoline maleate in the form of a yellow-brown powder, m.p. 169170C.

Anal. Calcd. for C, H N O .C H O C, 59.24; H, 6.71; N, 10.37. Found: C, 59.39; H, 6.69; N, 10.41.

EXAMPLE V1 The procedure described in Example 111 was repeated except that n-butyric anhydride was employed as reagent in place of acetic anhydride as reagent in the first step and there was ultimately obtained a 0.7 g. yield of 3-n-butyl-8-methyl-9-nitro-2,3,4,4a,5,6-hexahydro- 1H-pyrazino-[ l,2-a]-quino1ine maleate in the form of a yellow-brown powder, m.p. 183184C. after recrystallization from ethyl acetate-ethanol (9:1 by volume).

Anal. Calcd. for C,,H =,N O .C,H O C, 60.13; H, 6.97; N, 10.02. Found: C, 60.16; H, 7.05; N, 9.98.

EXAMPLE V11 The procedure described in Example IV was repeated except that N-cyclohexylethanolamine was employed as reagent in the first step instead of N- isopropylaminoethanol and there was obtained 2-N- cyclohexyl-N-hydroxyethylaminomethyl-6-methylquinoline as the resultant product. The latter was then reduced with Raney nickel, in the manner of Example IV, to give 2-Ncyclohexyl-N-B- hydroxyethylaminomethyl-6-methyl-1 ,2,3,4-tetrahydro quinoline, isolated as the maleate salt, m.p. 170172C. Cyclization with phosphoric oxide, as in the aforesaid example, then afforded a 50% yield of 3- cyclohexyl-8-methyl-2,3 ,4,4a,5 ,6-hexahydro-1H- pyrazino-[ 1 ,2-a]-quinoline maleate (m.p. 172.4174C.), which was subsequently converted to 3-cyclohexyl-8-methyl-9-nitro-2,3,4,4a,5,6-hexahydrolH-pyrazino-[ l,2-a]-quinoline maleate in a 1.2 g. yield. The latter product was obtained in the form of yellowish-brown needles, m.p. 213214C. after recrystallization from ethanol-ethyl cellusolve :1 by volume).

Anal. Calcd. for C H N -,O .C H O C, 62.00; H, 7.01; N, 9.43. Found: C, 61.72; N, 7.04; N, 9.29.

EXAMPLE V111 A solution consisting of 0.78 g. of 8-methyl-9nitro- 2,3,4,4a,5,6-hexahydro-1H-pyrazino-[ 1,2-a]-quinoline in 20 ml. of dry benzene containing 0.29 g. of triethylamine was stirred at 0C. in an ice-water bath, while 0.3 g. of ethyl chlorofonnate dissolved in 5 ml. of dry benzene was slowly added thereto during the course of a 30-minute period. The resulting mixture was then stirred for an additional 2 hours at ambient temperatures, filtered and the residue washed dry with diethyl ether. The combined washings and filtrate were then evaporated to near dryness under reduced pressure and the residual oil so obtained soon solidified. Recrystallization of the latter material from petroleum ether (b.p. 100C.), then gave 0.60 g. of 3-ethoxycarbonyl-8- methyl-9-nitro-2,3,4,4a,5 ,6-hexahydro- 1 H-pyrazino- [1,2-a]-quino1ine as bright yellow rosettes, m.p. 99C.

Anal. Calcd. for C H N O C, 60.64; H, 6.55; N, 13.04. Found: C, 60.20; H, 6.87; N, 12.77.

EXAMPLE 1X A solution of 11.5 g. of 8-methyl-9-nitro- 2,3,4,4a,5,6-hexahydro-1H-pyrazino-[ 1 ,2-a]-quino1ine in 100 ml. of acetic anhydride was refluxed for a period of 2 hours. The solution was then cooled and poured unto 500 g. of ice. In this way, the product crystallized on standing and was subsequently collected by means of suction filtration. After thoroughly washing the filter cake with water to remove excess acetic acid from same, the product was recrystallized from ethanol to afford 10.5 g. of pure 3-acetyl-8-methyl-9-nitro- 2,3,4,4a,5,6-hexahydro-1H-pyrazino-[ 1,2-a]- quinoline, m.p. l37-139C.

Anal. Calcd. for C H N O z C, 62.26; H, 6.62; N, 14.52. Found: C, 62.15; H, 6.55; N, 14.39.

EXAMPLE X A solution consisting of 0.80 g. of 3,8-dimethyl-9- nitro-2,3,4,4a,5,6-hexahydro-1H-pyrazino-[ 1 ,2-a]- quinoline dissolved in ml. of ethanol was hydrogenated over 80 mg. of 10% palladium-on-charcoal catalyst at 25C. and 100 p.s.i.g. pressure of hydrogen for a period of 3.5 hours. The catalyst was then removed by means of filtration and the solvent evaporated under reduced pressure to afford 3,8-dimethyl-9-amino- 2,3 ,4,4a,5,6-hexahydro-1H-pyrazino-[ l ,2-a]-quino1ine as a brown residual oil. The latter material, which was viscous in nature, was then dissolved in 1.3 m1. of concentrated hydrochloric acid and 1 g. of ice and subsequently treated a solution of mg. of sodium nitrite in 1.0 ml. of water while at 0C. The solution of the diazonium salt was then added at 0C. to a solution of freshly prepared cuprous chloride in 1.3 ml. of concentrated hydrochloric acid. The cuprous chloride had previously been obtained by mixing hot aqueous solutions of cupric sulfate (0.84 g.) and sodium chloride (0.22 g.) in 3.0 ml. of water with sodium metabisulfite (0.18 g.) and sodium hydroxide (0.12 g.) in 1.0 ml. of water, and thereafter washing the resulting pale green precipitate by means of decantation. At any rate, the resulting brown aqueous suspension, obtained as indicated above, was subsequently stirred and allowed to warm very slowly to room temperature (-25C.), at which point it was then heated to 60C. via a steambath and allowed to cool once again. The resulting solution was then basificd with 5N sodium hydroxide solution, extracted with diethyl ether and the combined ether extracts subsequently dried over anhydrous magnesium sulfate. Upon removal of the ether solvent by means of evaporation under reduced pressure, there was obtained 0.4 g of a brown oil as the residual liquid. The latter material was then chromatographed on neutral alumina, using chloroform as the eluent, to afford 150 mg. of a pale yellow oil, which consisted essentially of pure 3,8-dimethyl-9-ch1oro-2,3,4,4a,5,6-hexahydro- 1H-pyrazino-[ 1 ,2-a]-quinoline. Treatment of this compound in the usual manner with one equivalent of maleic acid, dissolved in warm ethyl acetate, then gave the corresponding maleate salt. Upon subsequent recrystallization of the latter material three times from ethyl acetate, there was finally obtained 100 mg. of pure 3,8- dimethyl-9-chloro-2,3 ,4,4a,5 ,6-hexahydro-1H- pyrazino-[ l ,2-a]-quinoline maleate in the form of small white crystals, m.p. l70l71C. (decomp.).

Anal. Calcd. for C H CIN C H O C, 58.94; H, 6.27; N, 7.64. Found: C, 59.11; H, 6.42; N, 7.41.

EXAMPLE Xl A solution consisting of 9.0 g. of 3-acetyl-8-methyl-9- nitro-2,3 ,4,4a,5,6-hexahydrol H-pyrazino-[ 1,2-a]- quinoline in 350 ml. of ethanol was treated with a suspension of Raney nickel (3 ml of settled nickel) and hydrogenated at 50C. under a pressure 750 p.s.i.g. for a period of 3 hours. The catalyst was then removed by means of filtration and the resulting filtrate evaporated to dryness while under reduced pressure. Recrystallization of the residue from ethanol then gave a 6.5 g. yield of 3-acetyl-8-methyl-9-amino-2,3,4,4a,5,6- hexahydrol H-pyrazino-[ 1,2-a]-quinoline, m.p. l97-l99C.

The above product (5.0 g.) was then diazotized and treated with cuprous choride in the same manner as described in the previous example for the corresponding 3-methyl compound. After basification with 5N sodium hydroxide solution, the resulting product was extracted into chloroform and the chloroform extracts subsequently washed with water, dried over anhydrous magnesium sulfate and filtered. The chloroform filtrate was then concentrated in vacuo and the residual oil so obtained (essentially, crude 8-methyl-9-chloro- 2,3,4,4a,5 ,6hexahydrol l-l-pyrazino-[ l,2-a]- quinoline) was taken up in a small amount of ethyl acetate. Treatment of the latter solution with a solution of maleic acid dissolved in ethyl acetate, then gave 8- methyl-9-chloro-2,3 ,4,4a,5,6-hexahydrol H-pyrazino- [l,2-a]-quinoline maleate as a crystalline precipitate. Recrystallization of the latter material from ethanol, after first washing with a fresh portion of ethyl acetate solvent by decantation, then afforded the pure maleate salt in 0.5 yield (m.p. 325C. with decomp. above 250C). On subsequent conversion to the corresponding hydrochloride and further recrystallization from ethanol, there was ultimately obtained pure S-methyl- 9-chloro-2,3 ,4,4a,5,6-hexahydrol H-pyrazino-[ l,2-a]- quinoline hydrochloride (m.p. $625C with decomp. above 260C).

Anal. Calcd. for C H CEN C, 57.1; H, 6.64; N, 9.82. Found: C, 57.05; H, 6.90; N, 9.82.

EXAMPLE Xll A solution consisting of 70 g. of 2,6-dimethyl-5- chloroquinoline dissolved in 600 ml. of dioxane was added rapidly to a well-stirred solution of selenium dioxide (60 g.) in a mixture of 500 ml. of dioxane and 24 ml. of water. The resulting mixture was then stirred and refluxed for a period of 3 hours, followed by cooling to room temperature and subsequent extraction with chloroform. The combined chloroform extracts were then dried over anhydrous magnesium sulfate and filtered, and the resulting filtrate thereafter concentrated in vacuo to afford a solid residue. Recrystallization of the latter material from ethyl acetate, in the presence of charcoal, then gave 55 g. of 5-chloro-6-methylquinoline-2-aldehyde as orange needles, mp l72-l73C.

The above aldehyde product (53 g.) was then dissolved in .750 m1. of boiling absolute ethanol and treated with 16 g. of ethanolamine, followed by continued boiling for a period of 2 hours. At this point, the resulting mixture was cooled and the precipitate subsequently removed by means of filtration to afford crude product. Upon recrystallization from 95% ethanol (1,500 ml.), there was obtained pure 2-(B- hydroxyethyliminomethyl)-5-chloro-6- methylquinoline, m.p. l76177C.

The latter product in 2 liters of ethanol was then treated with 40g. of sodium borohydride, with stirring and boiling under reflux, the borohydride reagent being added portion-wise over a period of 15 minutes. The resulting solution was then boiled under reflux for a further period of 3.5 hours, cooled and the excess borohydride thereafter decomposed by the addition of 250 ml. of 5N hydrochloric acid. After concentrating in vacuo, the solid residue so obtained was suspended in water and made alkaline with sodium hydroxide solution prior to extraction into chloroform. The chloroform solution was then washed with water, dried over anhydrous magnesium sulfate and filtered. Evaporation of the resulting filtrate to near dryness while under reduced pressurethan gave a solid residue, which was subsequently dissolved in a liter of ethanol and then treated with 50 ml. of concentrated hydrochloric acid. In this way, the product soon crystallized and was subsequently collected by means of filtration, washed with a little fresh ethanol and then dried to constant weight to afford 43 g. of 2-(B-hydroxyethylaminomethyl)-5- chloro-6-methylquinoline as the dihydrochloride salt, m.p. 193l96C.

A solution consisting 5 g. of the above product in 250 ml. of water was treated with Adams platinum oxide catalyst (0.2 g.) and hydrogenated at 25C. under a pressure of 30 p.s.i.g. of hyrogen for a period of 5.5 hours. The solution was then filtered to remove the catalyst and the filtrate subsequently made alkaline by the addition of aqueous sodium hydroxide solution. The product then separated from the solution as a gummy solid, which was thereafter extracted into chloroform. The chloroform extract thus obtained was washed with water and dried over anhydrous magnesium sulfate, and the subsequently dry filtrate thereafter concentrated in vacuo to afford a solid residue. Crystallization of the latter material from petroleum ether (b.p. 80l0OC.) then gave 3.2 g. of 2-( B- hydroxyethylaminoethyl )-5-chloro-6-methyll ,2,3 ,4- tetrahydro-quinoline. m.p. l l9122C.

A solution of 2.0 g. of 2-( B- hydroxyethylaminoethyl)-5-chloro-6methyl-1,2,3,4- tetrahydro-quinoline dissolved in 40 ml. of dry xylene was treated with 3.55 g. of phosphorus pentachloride and 2 g. of filter-aid. The mixture was then vigorously stirred and boiled under reflux for a period of 24 hours.

At the end of this period, the resulting mixture was cooled and slowly acidified with 500 ml. of 2N hydrochloric acid. As soon as all the black tarry residue had dissolved, the acidified mixture was filtered and extracted with diethyl ether. The aqueous solution which remained was then made alkaline with aqueous sodium hydroxide and extracted with diethyl ether once again. The combined ethereal extracts were washed with water, dried in the usual manner and subsequently con centrated in vacuo to afford a solid residual material, which consisted essentially of crude 7-chloro-8-methyl- 2,3,4,4a,5,6-hexahydrol H-pyrazino-[ 1 ,2-a] quinoline. Conversion of the latter material to the maleate salt, followed by recrystallization from ethanol then gave pure 7-chloro-8-methyl-2,3,4,4a,5,6- hexahydro- 1H-pyrazino-[ 1 ,2-a]-quinoline maleate, m.p. l89l90C.

Anal. Calcd. for C H C1N C H O C, 57.90; H, 6.0; N, 7.94. Found: C, 57.75; H, 5.94; N, 7.66.

EXAMPLE XIII Following the procedure described in the previous example, 2,6,8-trimethyl-7-chloroquinoline was con verted to 2-formyl-6,8-dimethyl-7-chloroquinoline to give a white solid material, melting at l47150C. after recrystallization from methanol. The latter product was then treated with ethanolamine in accordance with the same procedure and there was obtained 2-(13- hydroxyethylaminomethyl)-6,8-dimethyl-7- chloroquinoline as fawn plates, m.p. l22l23C. after recrystallization from methanol. Conversion of this material (3.6 g.) to the saturated product via hydrogenation over Raney nickel (l ml. suspension) at 75C. and 750 p.s.i.g. pressure for a period of 0.75 hours, then gave 2.4 g. of 2-(,B-hydroxythylaminomethyl)-6,8- dimethyl-7-chloro-l,2,3,4-tetrahydro-quinoline as an off-white solid, m.p. 109111C. Subsequent treatment of this latter product with phosphorus pentachloride, in the manner of Example XII, then afforded a 40% yield of 8,10-dimethyl-9-chl0ro-2,3,4,4a,5,6- hexahydro-lH-pyrazino-[1,2-a]-quinoline as a white powder, m.p. 94-96C. after recrystallization from methanol.

Anal. Calcd. for C H ClN C, 67.06; H, 7.59; N, 11.18. Found: C, 66.76; H, 7.39; N, 11.20.

EXAMPLE XIV A solution consisting of 1.6 g. of 8-methyl-9-nitro- 2,3 ,4,4a,5 ,6-hexahydro-1H-pyrazino-[ 1 ,2-a]-quinoline dissolved in ml. of dry benzene was treated with 0.7 g. of maleic anhydride dissolved in an equal amount of dry benzene (20 ml.). After allowing the reaction mixture to stand for 2 minutes at room temperature, a small amount of dark green oil formed and the solution was immediately separated from same by means of decantation. Soon afterwards, a deposit of yellow crystals formed from said solution and the entire mixture was then allowed to stand overnight at room temperature (-C.) for approximately 16 hours. The yellow crystals were subsequently collected by means of suction filtration and thereafter dried in vacuo to give 1.56 g.

4-(8-methyl-9-nitro-2,3,4,4a,5,6-hexahydro-1H- pyrazino-[ 1 ,2-a]-quinoline-3-yl )-4-oxocrotonic acid, m.p. 150-152C.

Anal. Calcd. for C H N O C, 59.12; H, 5.55; N, 12.17. Found: C, 58.80; H, 5.71; N, 11.72.

EXAMPLE XV A solution of 2.0 g. "at 8'-methyl-2,3,4,4a,5,6- hexahydro-lH-pyrazino-[ 1,2-a]-quinoline in ml. of absolute ethanol was treated with 2 ml. of 1-bromo-3- methylbutane and 2 g. of sodium carbonate, and the resulting mixture was stirred and refluxed for 24 hours. After cooling to room temperature and adding 200 ml. of dry diethyl ether to the mixture, the latter was filtered and the filtrate subsequently evaporated under reduced pressure to give an oily material as residue. The latter material was then taken up in 50 ml. of ethyl acetate, filtered again and the filtrate treated with a hot solution of 1.2 g. of maleic acid dissolved in ethyl acetate. On cooling, the resulting crystalline precipitate was collected by means of filtration and air-dried to give a 3.45 g. yield of 3-(3-methylbutyl)-8-methyl- 2,3,4,4a,5 ,6-hexahydrol H-pyrazino-[ l,2-a] -quinoline maleate, m.p. l69-170C.

The above product (3.4 g.) was then shaken between 200 ml. of 2N sodium hydroxide solution and 100 ml. of diethyl ether, and the ether layer subsequently separated, dried over anhydrous magnesium sulfate and filtered. The resulting filtrate was then evaporated under reduced pressure to give 2.0 g. of 3-(3-methylbutyl)-8- methyl-2,3,4,4a,5,6hexahydrol H-pyrazino'-[ 1,2-a]- quinoline as the residual oil. After nitration of the latter substance in the manner of Example 11 and subsequent converstion to the maleate, there was obtained 1.6 g. of 3(3-methylbutyl)-8-methyl-9-nitro-2,3,4,4a,5,6- hexahydro-1H-pyrazino-[ l,2-a]-quinoline maleate in the form of fluffly, bright-yellow needles, m.p. 2132l4C. after recrystallization from ethyl acetateethyl cellusolve (9:1 by volume).

Anal. Calcd. for C H N O C H O C, 60.95; H, 7.21; N, 9.69. Found: C, 60.75; H, 7.16; N, 9.48.

EXAMPLE XVI A solution consisting of 800 mg. of 8-methyl-9- chloro-2,3,4,4a,5,6-hexahydro-lH-pyrazino-[ l ,2-a]- quinoline dissolved in 60 ml. of absolute ethanol was treated with 0.46 ml. of n-propyl bromide and 800 mg of potassium carbonate and then refluxed for a period of 3 days. At the end of this time, two further quantities of n-propyl bromide (0.2 ml. each) in absolute ethanol (2 ml.) were added at 3-day intervals and after a period of 9 days, thin-layer chromotography indicated that the reaction was substantially complete. The excess potassium carbonate was then removed from the mixture by means of filtration and the ethanol solvent via evaporation under reduced pressure. Treatment of the residue with water and a few ml. of 5N sodium hydroxide to ensure complete basification, then gave an aqueous solution that was'subsequently extracted with diethyl ether. The combined ethereal extracts were then dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo to yield 0.4 g. of a brown oil,

which was essentially pure 3-n-propyl-8-methyl-9- chloro-2,3,4,4a,5 ,o-hexahydro-1H-pyrazino-[ l ,2-a]- quinoline. This product was then converted to the maleate salt in the usual manner, using 250 mg. of maleic acid in ethyl acetate as the reagent. After recrystallization from ethyl acetate, there was obtained 200 mg. of pure 3-n-propyl-8-methyl-9-chloro-2,3,4,4a,5,6- hexahydro- 1 H-pyrazino-l l,2-a]-quinoline maleate, m.p. 149-150c. l

Anal. Calcd. for c n cm c,H,o,; c, 60.83; H, 6.84; N, 7.10. Found: c. 60.82; H, 6.73; N, 6.94.

EXAMPLE XVII A solution consisting of 2.47 g. of 8-methyl-9-nitro- 2,3,4,4a,5,6-hexahydrol H-pyrazino-[ l ,2-a]-quinoline dissolved in 2.5 ml. of acetic anhydride was heated to l20-l25C. in an oil-bath. To this solution, there was then added 1.06 g. of acrylonitrile in a dropwise manner over a 2-hour period and the resulting dark solution was thereafter refluxed for 3 hours (using an oil-bath temperature of ca. 134C). The reaction mixture was then allowed to cool to room temperature and made alkaline with a saturated solution of potassium carbonate in water. The basified aqueous solution was next extracted with two-75 ml. portions of chloroform and the chloroform extracts were subsequently dried over anhydrous magnesium sulfate, filtered and thereafter concentrated in vacuo to yield a dark-red oil as residual liquid. The latter substance was taken up in ethanol, whereby a yellow crystalline material soon deposited from said solution. After collecting the crystals by means of filtration and recrystallizing same from ethanol, there was finally obtained a l.2 g. yield of 3-(ozcyanoethyl 8 -methyl-9-nitro-2,3 ,4,4a,5 ,6'hexahydrolH-pyrazino[ l ,2-a]-quinoline in the form of small yellow-brown cyrstals, m.p. llll 12C. (with softening at l lC).

Anal. Calcd. for C H N O C, 64.00; H, 6.67; N, l8.67. Found: C, 64.15; H, 6.73; N, 18.75.

EXAMPLE XVIII A cultureof Aspergillus Selerotiorum Huber is grown in several 300 ml. Erlenmeyer flasks each containing 50ml. aliquots of the hereinafter more fully described soybean-glucose nutrient medium, which had previously been sterilized via an autoclave l p.s.i.g. pressure for a period of 35 minutes. After shaking at 28C. for a period of 24 hours, via a shaker apparatus rotating at approximately 230 r.p.m., the resulting inoculum is added (at a level of 7.5% by volume) under sterile conditions and with constant agitation to a fermenter pot containing 2 liters of said same nutrient medium having the following composition:

Tap water, in sufficient amount for in l000 ml. solution adjusted to pH 6.5 with concentrated Sulfuric acid.

The inoculated medium in the fermenter is then agitated at 1,380 rpm. and simultaneously aerated with l-liter of air per minute at a temperature of 28C. for

a period of 47 hours. At the end of this period, the pH of the resulting medium is readjusted, if necessary, to pH 6.5 with added sulfuric acid. At this point, 0.75 g. of 3-n-propyl-8-methyl-9-nitro-2,3,4,4a,5,6-

hexahydrol H-pyrazino-[ l,2-a] -quinoline maleate, dissolved in 75 ml. of distilled water, is added to the mixture, and agitation and aeration are both thereafter continued for a period of 23 hours. On completion of this step, the pH is adjusted to pH 8.0 with sodium hydroxide and the mixture is then extracted exhaustively:

with several portions of methylene chloride. The combined organic extracts are next dried over anhydrous sodium sulfate and filtered, and the filtrate subsequently concentrated in vacuo to near dryness at a temperature below 40C.

The solid residue obtained in this manner is then ex- I tracted with methanol (total volume, 50 ml.) at room temperature, and the decanted extracts are subsequently filtered and treated with sodium borohydride, added in small portions over a period of 30 minutes with stirring, to reduce 8-formyl compound present in the mixture to the corresponding 8-hydroxymethyl compound. The so-treated methanol solution is then allowed to stand overnight 16 hours) at room temperature and diluted with five volumes of diethyl ether. After washing the resulting ethereal solution with water and drying over anhydrous magnesium sulfate, the ethereal filtrate is subjected to vacuum distillation in a water-bath at 40C. The residue afforded by this procedure is then taken up in isopropanol at 50C., filtered and thereafter cooled overnight in the refrigerator to give a yield of 3-n-propyl-8-hydroxymethyl-9-nitro- 2,3,4,4a,5 ,6-hexahydrol-H-pyrazino-[ l,2-a]-quinoline as crystalline precipitate.

In like manner, the other 8-hydroxymethyl compounds of the invention are similarly prepared using the appropriate 8-methyl-2,3 ,4,4a,5 ,6-hexahydro-l H- pyrazino-[l,2-a]-quinoline salt as substrate in each case.

EXAMPLE XIX Ten parts by weight of 3-n-propyl8-hydroxymethyl- 9-nitro-2,3,4,4a,5,6-hexahydrol I-I-pyrazino-[ l,2-a]- quinoline are added to a dried suspension of 25 parts by weight of active manganese dioxide in parts by volume of benzene and the mixture is stirred under reflux for 6 hours. After cooling, the mixture is filtered and the filtrate is evaporated to dryness to yield 3-npropyl-8-formyl-9-nitro-2,3 ,4,4a,5,6-hexahydrol H- pyrazino-[ l ,2-]-quinoline. In like manner, the other 8-formyl compounds of this invention are similarly prepared using the appropriate 8-methyl-2,3 ,4,4a,5,6-hexahydrol H-pyrazino-[ l ,2-a]- quinoline as startingmaterial in each case.

EXAMPLE xx Ten parts by weight of 3-npropyl-8-methyl-9-nitro- 2,3,4,4a,5,6-hexahydrol H-pyrazino-[ l ,2-a]-quinoline maleate in 50 parts by volume of water are neutralized with ION aqueous sodium hydroxide solution. Extraction of the resulting aqueous solution with several portions of methylene chloride, followed by separation of the organic layer and its subsequent concentration under reduced pressure then affords pure 3-n-propyl-8- 'methyl-9-nitro-2,3,4,4a,5 ,6-hexahydrol H-pyrazino- [l,2-a]-quinoline as a free organic base compound.

In like manner, when any of the other substituted hexahydro pyrazinoquinoline salts of this invention, like 8-methyl-9-chloro-2,3,4,4a,5 ,-hexahydrol H- pyrazino-[l,2-a]-quinoline hydrochloride of Example X], for instance, are each individually subjected to this very same reaction procedure, the corresponding free organic base compound is always the final product thus obtained.

EXAMPLE XXI The following substituted hexahydro pyrazinoquinoline compounds are prepared by employing the procedures described in the previous examples, starting from readily available materials in each instance:

EXAMPLE XXII A mixture of 2.0 g. of 3-n-propyl-8-methyl-9-nitro- 2,3 ,4,4a,5,6-hexahydrol H-pyrazino-[ l,2-a]-quinoline and a three molar excess of 30% hydrogen peroxide in ml. of acetone is stirred at room temperature (-25C.) for a period of 3 days. An additional quantity of 30% hydrogen peroxide (a five molar excess) is then added and the stirring thereafter continued for a further seven hours. At this point, the reaction is substantially complete and the excess hydrogen peroxide is decomposed by the addition of platinum oxide to the spent mixture. Upon filtering and removal of the solvent by concentration in vacuo, there is obtained a viscous oil as the liquid residue. Trituration of the latter material with diethyl ether then gives a powdery solid, which is subsequently collected by means of filtration and recrystallization from acetone to afford pure 3-npropyl-8-methyl-9-nitro-2 ,3 ,4,4a,5,6-hexahydrol pyrazino-[H-pyrazino-l-al-quinoline N-oxide as a crystalline solid.

In like manner, the other N-oxide compounds of this invention, where R is other than hydrogen, are each similarly formed by merely employing the appropriate 3-substituted 2,3,4,4a,5 ,o-hexahydrol H-pyrazinol ,2-a]-quinoline base as starting material in the above reaction procedure in place of the particular base compound used previously.

EXAMPLE XXIII The non-toxic hydrohalide acid addition salts of each of the substituted hexahydro pyrazinoquinoline bases reported previously in the preceding Examples, viz, the hydrochloride, hydrobromide, and hydroiodide salts, are each individually prepared by first dissolving the respective organic base compound in absolute ether followed by the introduction of the appropriate hydrogen halide gas into the reaction solution until saturation of same is complete with respect to said gas, whereupon the desired salt precipitates from said solution. The crystalline products so obtained are then subsequently recrystallized from acetone-diethyl ether to yield the pure hydrohalide salt in each case. For instance, when l.O g. of 3-n-propyl-8-methyl-9-nitro- 2,3,4,4a,5,6-hexahydrol H-pyrazino-[ l,2-a]-quinoline is dissolved in anhydrous diethyl ether and dry hydrogen chloride gas is subsequently passed into the resulting reaction solution until saturation of same is complete with respect to said gas, there is obtained a crystalline precipitate of 3-n-propyl-8-methyl- 9-nitro-2,3,4,4a,5,6-hexahydro-1H-pyrazino-[ 1,2-a] quinoline hydrochloride.

EXAMPLE XXIV The nitrate, sulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, gluconate, saccharate, gluconate, methanesulfonate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate salts of each of the substituted hexahydro pyrazinoquinoline bases previously described in Example XX XXI of the instant specification are all each individually prepared by separately dissolving in a suitable amount of ethanol the proper molar amounts of the respective acid and the appropriate organic base compound and then mixing the two solutions together, followed by the addition of diethyl ether to the resulting reaction solution in order to effeet precipitation of the desired acid additon salt therefrom. For instance, when equivalent amounts of 8- Inethyl-9chloro-2,3,4,4a,5 ,6-hexahydrol H-pyrazino- [l,2-a]-quinoline and concentrated sulfuric acid react in accordance with this procedure, the corresponding final product obtained is 8-methyl-9-chloro- 2',3,4,4a,5 ,6-hexahydrol H-pyrazino-[ l,2-a]-quinoline hydrogen sulfate. In like manner, each of the other acid addition salts is similarly obtained.

EXAMPLE XXV 8-Methyl-9-chloro-2,3 ,4,4a,5 ,6-hexahydro-1H- pyrazino-[ l,2-a]-quinoline hydrochloride (2.0 g., equivalent to 1.36 g. of the free organic base) was subjected to fermentative oxidation in the presence of Aspergillus sc'lerotiorum Huber, employing the procedure previously described in Example XXI of my copending U.S. patent application Ser. No. 732,850, filed May 29, 1968, with 0.5 g. of said starting material being added to each of the four fermenters as described therein. Upon evaporation of the dried methylene chloride extract. there were ultimately obtained 1.738 g. of a pale yellow solid powder melting at l55-l60C.

The latter was then dissolved in ml. of isopropanol at 60C. and the resulting solution thereafter refrigerated for a period of 3 hours. The precipitate which formed at this point was subsequently recovered by means of suction filtration and dried in vacuo at room temperature (25C.) to give a 0.4 g. yield of 8- hydroxymethyl-9-chloro-2,3 ,4,4a,5 ,6-hexahydro-1H- pyra zino-[1,2-a]-quinoline as an off-white powder, m.p. 168-169C. A further 0.15 g. of material (m.p. 168l69C.) was obtained from the mother liquor on evaporation of said filtrate at room temperature to give a total conversion yield of 44%.

Anal. Calcd. for C, H, C1N O: C, 61.77; H, 6.78; N, 11.09. Found: C, 61.99; H, 6.55; N, 10.59.

EXAMPLE XXVI 2-(N,N-Diethylaminomethyl)-6'Methyl-7-Nitrol ,2,3,4-Tetrahydroquinoline 1. 200 g. of 6-methylquinoline-2-carboxylic acid is suspended in 5 liters of dry toluene and treated with phosphorus pentachloride (1 mole per mole of acid) and refluxed for 2 hours. After decolorizing with charcoal and filtering, the solution of the acid chloride so formed is cooled to room temperature in the absence of moisture and then added to a solution of diethylamine (2 moles per mole of original acid) in dry toluene (3volumes per volume of diethylamine). The bright red product is stirred for one-half hour and then washed with water and dried over anhydrous sodium sulfate. After distilling off the toluene in vacuo, the solid residue is crystallized from ethanol to yield 2-(N,N- diethylcarbamoyl)-6-methylquinoline (m.p. l 17-1 19, overall yield 65-75%).

2. A solution of 35 g. of the product of( 1 in 350 ml. of dry dioxan is added slowly to a stirred suspension of lithium aluminum-hydride-[ l .5 moles per mole of product of(1)] in dry dioxan ml. per g. of LiAlH The mixture is stirred at reflux temperature for 5 hours and then cooled in an ice bath. Water is added cautiously to destroy excess LiAlH,. After filtration, the solution is distilled in vacuo to dryness. The residual oil g.) is dissolved in 450 ml. of methanol and hydrogenated in an autoclave at 75 and 750 p.s.i. in the presence of Raney nickel for 4 hours. The product is cooled to room temperature, filtered and distilled in vacuo to yield 2-(N,N-diethylaminoethyl)-6-methyl- 1,2,3,4-tetrahydroquinoline [b.p. 120-130 at 0.2 mm. Hg.: overall yield of stage (2) 3550%].

3. 20 g. of the product of (2) is added dropwise to 500 ml. of concentrated sulfuric acid cooled in ice and stirred during the addition. The mixture is then warmed gently to 20 to form a clear solution, cooled again in ice to below 5C. and treated with a 10% solution of fuming nitric acid [S.g. 1.5, 1 mole per mole of product of (2)] in conc., sulphuric acid, added dropwise with stirring to keep the temperature below 5C. After stirring on the ice bath for a further 3 hours, the solution is poured onto ice and neutralized with sodium bicarbonate. The product separated as a red oil, together with sodium sulfate, and is collected by filtering and washing with ether. The filtrate is extracted with ether and the combined ether extracts and washings are dried to yield 2-( N,N-diethylaminomethyl )-6'methyl-7nitro- 1,2,3,4-tetrahydroquinoline as a red oil, which is crystallized from 60/80 petrol-ether at 80 in a bath of chloroform and solid carbon dioxide. After drying, the product had a melting point of 5254 (yield 50%), having the following analysis:

Found: C: 64.86%; H: 833%; N: 14.95%. Required for C, ,H,,N,,o c; 64.9%; H: 8.35%; N: 15.15%

EXAMPLE XXVll 2-lsopropylaminomethyl-6-methyl-7-nitro-1 ,2,3,4- tetrahydroquinoline l. 2,6-Dimethylquinoiline (314 g. 2 moles) is dissolved in 1 liter carbon tetrachloride and sodium carbonate (200 g.) added, stirred and warmed to 60C. Heat is removed and chlorine passed into the solution at 300400 nil/min, the temperature being controlled at about 60C. After 5 /2 hours reaction is complete and the product starts crystallizing out of solution. The reaction products are then cooled and poured into 1 liter of 2N hydrochloric acid. The organic layer is separated and extracted 3 times with 1 liter of 2N hydrochloric acid. The combined acid layers are washed with methylene dichloride (500 ml.) and then basified with sodium carbonate, when 2-chloromethyl-6- methylquinoline separated as a pale buff solid. Filtration and drying yielded 348 g. of m.pt. 108110C.

2. 250 g. of the product of 1 is added over one-half hour to a stirred solution of isopropylamine 1.25 liter) in methylated spirit 1.25 liter) and stirred for a further hour. After standing for 18 hours, the solution is treated with charcoal and filtered. Evaporation to a thick slurry is followed by partitioning between 1 liter each of water and methylene dichloride. The aqueous layer is separated and extracted twice with 500 ml. methylene dichloride. The combined organic layers are dried and evaporated to yield 2' isopropylaminornethyl-6-methylquinoline as a dark oil (249 g.).

3. 235 g. of the product of (2) are dissolved in 1.4 liter methylated spirit and hydrogenated in the presence of Raney nickel at 750 p.s.i. and C. (complete after 2 /2 hours). After filtration and cooling to 0, g. conc. H- SO are added dropwise over one-half hour, further solvent being added as necessary. The precipitate is then filtered, washed with acetone and ether, and dried to yield 300 g. of 2-isopropylaminomethyl-6- methyl-1,2,3,4-tetrahydroquinoline hydrogen sulfate as a white amorphous solid (m.pt. 158).

4. 253 g. of the product of (3) is nitrated as described in Example XXVI, (3), except that neutralization is carried out with ION sodium hydroxide. The orange oily product is extracted into methylene dichloride, evaporated, re-dissolved in ethyl acetate, dried and evaporated, and then converted to the maleate salt by conventional means. Crystallization from methylated spirit yielded 144 g. of 2- isopropylamino' methyl-6-methyl-7-nitro-1 ,2,3 ,4-tetrahydroquinoline hydrogen maleate ,as dark brown needles (m.pt. 1834).

Analysis: found: C, 57.06; H, 6.50; N, 1 1.14% Calcd. for C H N O C, 57.01; H, 6.60; N, 11.08%

EXAMPLE XXVlIl 2-( N-t-Butylaminomethyl )-6-methyl-7-nitro- 1 ,2,3,4-tetrahydroquinoline 1. A mixture of 2-formyl-6-methylquinoline (10.25 g.; 0.06 m) and tertiary butylamino (17.52 g.; 0.24 m) in absolute alcohol 200 cc.) is hydrogenated over 5% palladium on barium sulfate catalyst 10 g.) at 50 p.s.i.

' for one hour. The catalyst is removed by filtration and evaporation of the solvent .yielded a brown mobile oil which is distilled to give 2-( N-tcrtbutylaminomethyl-6-methylquinoline as a goldenyellow mobile oil of b.pt. l42/0.7 mm. Hg (yield 1 1.7 g.).

2. 10 g. of the product of 1) in ethanol (175 cc.) is hydrogenated over Raney nickel (2 c.c.) at 75 and 750 p.s.i. for 4 hours. The catalyst is removed by filtration and the alcohol evaporated in vacuo to yield an oil which is fractionally distilled to give Z-(N-tertiary butylaminomethyl )-6-methyl- 1,2,3,4-tetrahydroquinoline of b.pt. mm. Hg. (yield 8.6 g.).

3. 5.34 g. of the product of(2) is nitrated as in Exam ple XXVI (3). The dark red oil product is extracted into chloroform, dried, evaporated in vacuo and then chromatographed on a column of neutral alumina. Elution with 50% mixture of benzene and chloroform removes an orange band and evaporation of the solvent gives 2-( N-tert-butylaminomethyl )-6 methy1-7-nitro-1,2,3,4-tetrahydroquinoline as a bright red solid of m.pt. 6368.

Analysis: found: C, 64.60; H, 8.10; N, 15.35% C H23N3O2 requires C, 65.00; H, 8.30; N, 15.16%

EXAMPLE XXIX 7-Chloro-2-diethylaminomethyl-6-methyl-1,2,3 ,4- tetrahydroquinoline A solution of 10 g. of 2-bromomethyl-7-chloro-6- methylquinoline in a mixture of 100 ml. ethanol and 200 ml. chloroform at room temperature is added over a period of 5 minutes to a solution of 8.1 g of diethylamine in 100 ml. ethanol with stirring. The solution is then allowed to stand at room temperature for hours and the solvents are distilled off under vacuum. The oily residue is triturated with about 100 ml. water, the product extracted into chloroform and traces of excess diethylamine removed by washing the chloroform solution with water three times. The chloroform solution is then dried over magnesium sulfate and distilled in vacuo to dryness. The residual oil is dissolved in about 200 ml. dry ether and dry hydrogen chloride gas is bubbled through the solution to precipitate 7-chloro-2- dimethylaminomethyl-6-methylquinoline hydrochloride. The salt crystallized on standing and is collected and recrystallized from ethanol, with a little ether added to ensure a good recovery of product. This gave 6.6 g. of white crystalline material of m.pt. 196202C.

2. The product of l is hydrogenated in the presence of Raney nickel as described in Example XXVlll. The green residue after evaporation of the ethanol is triturated with an ethyl acetate/ligroin mixture until asolid crystalline product is obtained. This product recrystal lizes from iso-propanol/ether to give 7-chloro-2- diethylaminoethyl-6-methyll,2,3,4-tetrahydroquinoline hydrochloride a white crystalline product of m.pt. 1723.

Analysis: found: C. 58.97; H, 7.99; N, 9.00% Calcd.

for C H Cl N C, 59.4; H, 8.0; N, 9.25%

EXAMPLE XXX Z-Diethylaminomethyl-4,6-dimethyl-7-nitro- 1 ,2,3,4- tetrahydroquinoline l. 2,4,6-trimethylquinoline (40 g., 0.234 mole) is chlorinated in a manner analogous to that described in Example XXVll l to give 2-chloromethyl-4,6- dimethylquinoline as a buff colored powder. Recrystallization from 40/60C. petroleum ether gives 23 g. of very pale, yellow needles, mp. 6061.

2. 15 g. of the product of (1) suspended in absolute ethanol 100 ml.) is treated with diethylamine (20 ml., 14.2 g.) and complete dissolution brought about by warming. The mixture is then left to stand overnight and the ethanol distilled off under reduced pressure. The semi-solid residue is treated with excess 2N sodium hydroxide solution and extracted with two 200 ml. portions of ether. The combined extracts are dried over magnesium sulfate, the ether evaporated off and the residual oil fractionated under reduced pressure. 2- Diethylaminomethyl-4,-dimethylquinoline distilled at 1 19/0.18 mm. Hg. as a very pale yellow oil.

3. 15 g. of the product of (2) is hydrogenated as described in Example XXVlIl (2), fractional distillation yielding 3.7 g. of 2,4,6-trimethyl- 1 ,2,3,4- tetrahydroquinoline (b.p. 901 10 at 1.0-1.5 mm. Hg.) and 2.0 g. of 2-diethylaminomethyl-4,6- dimethyl-1,2,3,4-tetrahydroquinoline as a pale yellow oil (b.p. 112 at 0.20 mm. Hg).

4. 1.5 g. of the latter product of (3) is nitrated and converted to the maleate salt as in Example'XXVll (4) and recrystallized from ethyl acetate, containing a trace of methanol, to yield 0.65 g. of 2- diethylaminomethyl-4,6dimethyl-7-nitro- 1 ,2,3,4- tetrahydroquinoline hydrogen maleate as red needles, mp. l312.

Analysis: found: C, 58.80; H, 7.08; N, 10.17% Calcd. for C H N O C, 58.95; H, 7.17; N, 10.31%

EXAMPLE XXXI tained 2.0 liters of the following medium, sterilized for 35 minutes at 15 p.s.i.

Soybean meal Glucose NaCl K HPO Yeast Extract Tap water to M F-LIILIILIICLII :UQUQOGOQOO pH adjusted with sulphuric acid to 6.5

The fermcnters are inoculated with 7.5% by volume of a 24 hour old culture of Aspergillus sclerotiorum Huber grown at 28C. in 50 ml. aliquots of the above described soybean-glucose medium contained in 300 ml. Erlenmeyer flasks, placed on a shaker rotating at approximately 230 rpm. The inoculated fermcnters are agitated at 1,380 rpm. and each aerated with 1 liter of air per minute and at a temperature of 28C. for 47 hours. A silicone anti-foam is added when required. At the end of the 47 hour period, the pH of the fermentation broth rose to 6.8-6.9. Sulfuric acid is added with sterile precautions to restore the pH to 6.5.

2. 0.75 g. of the produce of Example XXVll as hydrogen maleate, dissolved in ml. of sterile water is added to each of the four fermcnters and agitation and aeration are continued for a further 23 hours. The whole fermentation broths from each fermenter are pooled, the pH adjusted to 8.0with sodium hydroxide and the 8.2 liters of fermentation broth thus obtained are extracted by agitating vigorously with 16.4 liters of methylene chloride for 10 minutes. The solvent extract is dried over anhydrous sodium sulfate and then evaporated to dryness at a temperature below 40C. (dry weight 5.567 g.).

3. The dark brown residue from (2) is extracted four times with methanol at room temperature, decanting the solution from the insoluble material. The combined methanol extracts, total volume about 200 ml. are then filtered and treated with 3 g. sodium borohydride, added in portions over a period of minutes with stirring, to reduce any 6-formyl compound present to the 6-hydroxymethyl compound. The methanol solution is allowed to stand overnight at room temperature and is then diluted with 1 liter of ether. The solution is washed 4 times with 500 ml. water and the resulting pale yellow ethereal solution is dried over magnesium sulfate. The ether is removed by vacuum distillation from a water bath at The residue is dissolved in about 75 ml. isopropanol at 50C., filtered to remove any insoluble particles and cooled overnight in the refrigerator. The product is collected and dried in vacuo to yield 0.5 g. of 6-hydroxymethyl- 2-isopropylaminoethyl-7-nitro- 1 ,2,3,4- tetrahydroquinoline as pale yellow crystals of m.pt. l47-9C. A further 0.5 g. of crude material is obtained from the mother liquors of the recrystallization. Total yield is therefore 1.0 g. (0.0036 mole) from 3.0 g. (0.0079 mole) of starting material, i.e., of theoretical.

Analysis: Found: C, 59.93; H, 7.84; N, 14.82% Calcd. for C H N O C, 60.15; H, 7.58; N. 15.04%

LII

What is claimed is:

l. A hexahydro pyrazinoquinoline compound selected from the group consisting of 7-nitro-8-hydroxymethyl-2,3,4.4a,5,6- hexahydrol H-pyrazin0-[ l ,2-a]-quinoline, 8-hydroxymethyl-9-nitro 2.3,4,4a.5.6-hexahydrol H-pyrazino-[ l,2-a]- quinoline, 3-n-propyl- 8-hydroxymethyl-9-nitro-2,3,4,4a,5 ,6-hexahydro-1H- pyrazino-[ l ,2-a]-quinoline, 3-isopropyl-8- hydroxymethyl-9-nitro-2, 3 ,4,4a,5 ,6- hexahydro-l H-pyrazino-[ l,2-a]-quinoline, 7-chloro-8- hydroxymethyl- 2,3,4,4a,5,6hexahydro-l H-pyrazino-[ l ,2-a]- quinoline, 8-hydroxymethyl-9-chloro-2,3,4,4a,5 ,6-hexahydrol H pyrazinol ,2-a]-quinoline, 3-methyl-8-hydroxymethyl-9- chloro-2,3,4,4a,5,6- hexahydrol H-pyrazino-[ l,2-a]-quinoline, 8-hydroxymethyl-9-chlorolO-methyl-2,3 ,4,4a,5,6-hexahydrol H-pyrazino-[ l ,2- a]-quinoline and 3-n-propyl-S-hydroxymethyl-9- chloro-2,3,4,4a,5,o-hexahydrol H-pyrazino-[ l,2-a]-quinoline.

2. 8-Hydroxymethyl-9-chloro-2,3,4,4a,5,6-hexahydro-lH-pyrazino-[l,2-a]-quinoline, a compound of claim 1.

3. 3-n-Propyl-8-hydroxymethyl-9-nitro-2,3,4,4a,5,6- hexahydrol H-pyrazino-l l,2a]-quinoline. a compound of claim 1. 

1. A HEXAHYDRO PYRAZINOQUINOLINE COMPOUND SELECTED FROM THE GROUP CONSISTING OF 7-NITRO-8-HYDROXYMETHYL-2,3,4,4A,5,6HEXAHYDRO-1H-PYRAZINO-(1,2-A)-QUINOLINE. 8-HYDROXYMETHYL9-NITR-2,3,4,4A,5,6,-HEXAHYDRO- (H-PYRAZINO-)1,2,-A(-QUINOLINE, 3-N-PROPL-8-HYDROXYMETHYL-9-NITRO-2,3,4,4A,5,6,-HEXAHYDRO-1H-PYRAZINO-(1,2 -A)-QUINOLINE, 3-ISOPROPYL-8-HYDROXYMETHYL-9-NITRO-2,3,4,4A,5,6-HEXAHYDRO-1H-PYRAZINO-(1,2 -A)QUINOLINE,7-CHLORO-8-HYDROXYMETHYL-2,3,4,4A,5,6-HEXAHYDRO1H-PYRAZINO -(1,2,-A)-QUINOLINE, 8-HYDROXY-METHYL-9-CHLORO2,3,484A,5,6-HEXAHYDRO- H-PYRAZINO-(1,2-A)-QUINOLINE, 3METHYL-,-HYDROXYMETHYL-."-CHLORO-2,3,4,4A,5,6-HEXAHYDRO1H-PYRAZINO-(U,2,A) -QUINOLINE 8-HYDROXYMETHYL-9-CHLORO10-METHYL-2,3,4,4A,5,6-HEXAHYDRO- 1H-PYRAZINO-( 1,2,-A)QUINOLINE AND 3-N-PROPYL-8-HYDRIOXYMETHYL-.-CHLORO2,3,4,4A,5,6-HEXAHYDRO-1H-PYRAZIN-(1,2, -A)-QUINOLINE,
 2. 8-Hydroxymethyl-9-chloro-2,3,4,4a,5,6-hexahydro-1H-pyrazino-(1,2-a) -quinoline, a compound of claim
 1. 3. 3-n-Propyl-8-hydroxymethyl-9-nitro-2,3,4,4a,5,6-hexahydro-1H-pyrazino-(1,2 -a)-quinoline, a compound of claim
 1. 